Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1.

The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.

BACKGROUND AND PURPOSE: Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. EXPERIMENTAL APPROACH: We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. KEY RESULTS: Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). CONCLUSIONS AND IMPLICATIONS: The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation.

The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide.

Interventions for treating oral lichen planus: a systematic review.

Oral lichen planus (OLP) is a common chronic inflammatory disease associated with cell-mediated immunological dysfunction. Symptomatic OLP is painful and complete healing is rare. The aim of this review was to assess the evidence for the efficacy and safety of treatments for symptomatic OLP. The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched in January 2011 to identify all randomized controlled trials (RCTs) evaluating any intervention for the treatment of symptomatic OLP. A total of 28 trials were included in this Cochrane review. There was no evidence from three RCTs that topical pimecrolimus is better than placebo in reducing pain from OLP. There was weak evidence from two RCTs that topical aloe vera may be associated with a reduction in pain compared with placebo. There was weak and unreliable evidence from two small trials, at high risk of bias, that topical ciclosporin may reduce pain and clinical signs of OLP. There was no evidence (from five trials each evaluating a different steroid and/or calcineurin inhibitor) that there is a difference between treatment with topical corticosteroids (TCSs) compared with topical calcineurin inhibitors with regard to reducing pain associated with OLP or that any specific steroid therapy is more or less effective at reducing pain. Although TCSs are considered to be the first-line treatment, we did not identify any RCTs that compared TCSs with placebo in patients with symptomatic OLP. From the 28 trials included in this systematic review, the wide range of interventions compared means there is insufficient evidence to support the superior effectiveness of any specific treatment.

Laparoscopy versus laparotomy for benign ovarian tumor: a systematic review and meta-analysis.

To determine the efficacy, safety, and cost of laparoscopic surgery compared with laparotomy in women with ovarian tumors assumed to be benign. This study is a systematic review. We searched (MEDLINE, EMBASE, LILACS, and COCHRANE LIBRARY) trials registers and reference lists of published trial reports. Six randomized controlled trials were identified involving 324 patients. Duration of surgery, adverse effects of surgery, pain, length of hospital stay, and economic outcomes were compared. The mean duration of surgery was longer in the laparoscopy group overall (weighted mean difference 11.39, 95% CI 0.57-22.22). The pooled estimate for febrile morbidity decreased for laparoscopy (Peto OR 0.34, 95% CI 0.13-0.88). The odds of any adverse effect were decreased after laparoscopic procedures (Peto OR 0.26, 95% CI 0.12-0.55). The odds of being pain free were significantly greater for the laparoscopy group (Peto OR 7.35, 95% CI 4.3-12.56). Mean length of hospital stay was shorter in the laparoscopy group with reduction of 2.79 days (95% CI -2.95 to -2.62). In economic outcomes, there was a significant reduction of US$1045 (95% CI -1361 to -726.97) in the laparoscopy group. Laparoscopy is associated with a reduction in the following: febrile morbidity, urinary tract infection, postoperative complications, postoperative pain, days in hospital, and total cost. These findings should be interpreted with caution as only a small number of studies were identified including a total of only 324 women.

Laparoscopy versus laparotomy for benign ovarian tumours.

BACKGROUND: Over the last ten years laparoscopy has become an increasingly common approach for the surgical removal of benign ovarian tumours. There remains uncertainty as to the value of this intervention. This review has been undertaken to assess the available evidence for the benefits and harms of laparoscopic surgery for benign ovarian tumours compared to laparotomy. OBJECTIVES: To determine the efficacy, safety and cost of laparoscopic surgery compared with laparotomy in women with ovarian tumours assumed to be benign. SEARCH STRATEGY: We searched electronic databases, trials registers and reference lists of published trial reports. Review articles were also searched. SELECTION CRITERIA: All randomised controlled trials comparing laparoscopy versus laparotomy for benign ovarian tumours. DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed each study's eligibility and quality and extracted data. MAIN RESULTS: Six randomised controlled trials were identified involving 324 patients. Three subgroups of ovarian tumours were considered: any histological type of benign ovarian tumour, dermoid cysts and endometriomata. Surgical outcomes: The mean duration of surgery was longer in the laparoscopy group compared to the laparotomy group overall (WMD 11.39; 95% CI 0.57 to 22.22). However, heterogeneity was present with substantial inconsistency (I(2)=87%) . The heterogeneity found in these analyses was likely to reflect differences in the patient populations. Adverse effects of surgery: The pooled estimate for febrile morbidity decreased for laparoscopy compared to laparotomy (Peto OR 0.34; 95% CI 0.13 to 0.88). The odds of any adverse effect of surgery (total number of complications - surgical injury and/or post operative complications) were decreased after laparoscopic procedures (Peto OR 0.26; 95% CI 0.12 to 0.55). Short-term recovery: VAS pain scores favoured laparoscopy (WMD -2.36; 95% CI -2.07 to -2.03) andt he odds of being pain free were significantly greater for the laparoscopy group compared to laparotomy (Peto OR 7.35; 95% CI 4.3 to 12.56). Mean length of hospital stay was shorter in the laparoscopy group with reduction 2.79 days (95% CI -2.95 to -2.62) compared to laparotomy. Economic outcomes: There was a significant reduction of US$1045 (95% CI -1361 to -726.97) in the laparoscopy group compared to the laparotomy group in one trial of women with any type of benign ovarian tumour. AUTHORS' CONCLUSIONS: In women undergoing surgery for benign ovarian tumours, laparoscopy is associated with a reduction in the following; febrile morbidity, urinary tract infection, post operative complications, post operative pain, days in hospital and total cost. These findings should be interpreted with caution as only a small number of studies were identified including a total of only 324 women and not all of the important outcomes were reported in each study.

Pre and post operative medical therapy for endometriosis surgery.

BACKGROUND: Endometriosis is a common gynaecological condition which affects approximately 10% of women of reproductive age (Askenazi 1997). There is a range of symptoms and most commonly women present with dysmenorrhoea, pelvic pain, infertility or a pelvic mass. Direct visualisation and biopsy during laparoscopy or laparotomy is the gold standard diagnostic test for this condition and enables the gynaecologist to identify the location, extent and severity of the disease. Surgical therapy can be performed concurrently with diagnostic surgery and may include removal (excision) or destruction (ablation) of endometriotic tissue, division of adhesions and removal of endometriotic cysts. Laparoscopic excision or ablation of endometriosis has been shown to be effective in the management of pain in mild-moderate endometriosis. Adjunctive medical treatment pre or post-operatively may prolong the symptom-free interval. OBJECTIVES: To determine the effectiveness of systemic medical therapies used for hormonal suppression before or after surgery for endometriosis, or before and after surgery for endometriosis in the eradication of endometriosis, improvement of symptoms, pregnancy rates and overall tolerability by comparing them with no treatment or placebo. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility group trials register (searched 10 September 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3 2003), MEDLINE (January 1966 to September 2003), EMBASE (January 1985 to September 2003) and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Trials were included if they were randomised controlled trials of the use of systemic medical therapies for hormonal suppression before or after, or before and after surgery for endometriosis. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment was performed independently by using relative risk or weighted mean difference and 95% confidence intervals. MAIN RESULTS: Eleven trials were included in the review. One study comparing pre-surgical medical therapy with surgery alone showed a significant improvement in AFS scores in the medical therapy group (WMD -9.60, 95% CI -11.42 to -7.78) but this may or may not be associated with better outcomes for the patients. Post surgical hormonal suppression of endometriosis compared to surgery alone (either no medical therapy or placebo) showed no benefit for the outcomes of pain or pregnancy rates but a significant improvement in disease recurrence (AFS scores (WMD -2.30, 95% CI -4.02 to -0.58)). There were no trials identified in the search that compared hormonal suppression of endometriosis before and after surgery with surgery alone. There is no significant difference between pre surgery hormonal suppression and post surgery hormonal suppression for the outcome of pain in the one trial identified (RR 1.01, 95% CI 0.49 to 2.07). Information concerning AFS scores and ease of surgery was reported only as a descriptive summary so any difference between the groups can not be quantified from the information in the report of this trial. REVIEWERS' CONCLUSIONS: There is insufficient evidence from the studies identified to conclude that hormonal suppression in association with surgery for endometriosis is associated with a significant benefit with regard to any of the outcomes identified. There may be a benefit of improvement in AFS scores with the pre-surgical use of medical therapy. The possible benefit should be weighed in the context of the adverse effects and costs of these therapies.